Nature Immunology
1, 489 - 495 (2000)
doi:10.1038/82732
Fas triggers an alternative, caspase-8−independent cell death pathway using the kinase RIP as effector moleculeNils Holler1, Rossana Zaru1, Olivier Micheau1, Margot Thome1, Antoine Attinger1, Salvatore Valitutti1, Jean-Luc Bodmer1, Pascal Schneider1, Brian Seed2
& Jürg Tschopp11
Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. 2
Department of Molecular Biology, Massachussets General Hospital, Boston, MA 02114, USA.
Correspondence should be addressed to Jürg Tschopp jurg.tschopp@ib.unil.chCell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic signaling pathway remains largely uncharacterized. We show here that Fas kills activated primary T cells efficiently in the absence of active caspases, which results in necrotic morphological changes and late mitochondrial damage but no cytochrome c release. This Fas ligand−induced caspase-independent death is absent in T cells that are deficient in either Fas-associated death domain (FADD) or receptor-interacting protein (RIP). RIP is also required for necrotic death induced by tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). In contrast to its role in nuclear factor  B activation, RIP requires its own kinase activity for death signaling. Thus, Fas, TRAIL and TNF receptors can initiate cell death by two alternative pathways, one relying on caspase-8 and the other dependent on the kinase RIP.
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